title: Mineralocorticoid receptor interaction with SP1 generates a new response element for pathophysiologically relevant gene expression.
abstract: The mineralocorticoid receptor (MR) is a ligand-induced transcription factor belonging to the steroid receptor family and involved in water-electrolyte homeostasis, blood pressure regulation, inflammation and fibrosis in the renocardiovascular system. The MR shares a common hormone-response-element with the glucocorticoid receptor but nevertheless elicits MR-specific effects including enhanced epidermal growth factor receptor (EGFR) expression via unknown mechanisms. The EGFR is a receptor tyrosine kinase that leads to activation of MAP kinases, but that can also function as a signal transducer for other signaling pathways. In the present study, we mechanistically investigate the interaction between a newly discovered MR- but not glucocorticoid receptor- responsive-element (=MRE1) of the EGFR promoter, specificity protein 1 (SP1) and MR to gain general insights into MR-specificity. Biological relevance of the interaction for EGFR expression and consequently for different signaling pathways in general is demonstrated in human, rat and murine vascular smooth muscle cells and cells of EGFR knockout mice. A genome-wide promoter search for identical binding regions followed by quantitative PCR validation suggests that the identified MR-SP1-MRE1 interaction might be applicable to other genes. Overall, a novel principle of MR-specific gene expression is explored that applies to the pathophysiologically relevant expression of the EGFR and potentially also to other genes.
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, 06112 Halle/Saale, Germany, Institut für Informatik, Universität Halle-Wittenberg, 06120 Halle/Saale, Germany and Abteilung Molekulare Genetik, Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung (IPK), 06466 Gatersleben, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meinel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ruhs
authors.forename: Katja
authors.initials: K
authors.lastname: Schumann
authors.forename: Nicole
authors.initials: N
authors.lastname: Strätz
authors.forename: Kay
authors.initials: K
authors.lastname: Trenkmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Schreier
authors.forename: Ivo
authors.initials: I
authors.lastname: Grosse
authors.forename: Jens
authors.initials: J
authors.lastname: Keilwagen
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
authors.forename: Claudia
authors.initials: C
authors.lastname: Grossmann
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D018161:Receptors, Mineralocorticoid; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D000450:Aldosterone; D066246:ErbB Receptors